Schizophrenia is a pan-cerebral illness, affecting almost every modality, function, and brain region studied. While each symptom and function might be due to its own failed mechanism, parsimony encourages us to find an elemental mechanism that could be at the root of at least some of the symptoms. Evidence is accumulating that schizophrenia is characterized by dysfunction of efference copy/corollary discharge mechanisms that normally allow us to unconsciously recognize and disregard sensations resulting from our own actions. This dysfunction may give rise to subtle but pervasive sensory/perceptual aberrations in schizophrenic patients, altering their experience of their own overt and covert actions, as well as their interactions with the environment. It may also contribute to symptoms such as hallucinations, delusions, and even the desire to engage with people and in activities. In the initial funding period, we developed neurophysiological paradigms to study motor-sensory feed- forward processes, or efference copy/corollary discharge mechanisms, in the speech-auditory system, and showed these processes to be deficient in chronic schizophrenia. Specifically, we were able to observe neural responses during talking, which made evident the consequences of the successful action of the corollary discharge. We have also developed a method to observe synchronous neural activity preceding talking, which we believe reflects the efference copy in action. Recently, we extended this neurophysiological research to the somatosensory system, and again we find evidence of deficient motor-sensory feedforward processes in schizophrenia. If dysfunction of this elementary mechanism is reliable, valid, and not the result of antipsychotic medications, it might represent a major new class of electrophysiological measures sensitive to a fundamental and ubiquitous pathophysiological process in schizophrenia. Accordingly, these measures may serve as novel neurophysiological endophenotypes for identifying genes that confer risk for schizophrenia. They may also be useful as outcome measures during the development and testing of novel treatments for schizophrenia. To begin to address these important possibilities, we propose to continue our studies of the efference copy/corollary discharge system and its abnormalities in schizophrenia, across auditory, somatosensory and visual modalities. We propose to assess patients during early stages of the illness and more chronic phases to assess the effects of illness duration. We will also assess unaffected first-degree relatives of schizophrenic patients in order to determine whether these corollary discharge abnormalities reflect genetic risk for the illness. Finally, proposed studies of neurosurgery patients implanted with cortical electrodes will allow us to localize the origins and destinations of these efference copy/corollary discharge feed-forward signals. This information will help us to better localize the brain regions and circuitry that may underlie corollary discharge dysfunction in schizophrenia. PUBLIC HEALTH RELEVANCE We have developed a brain imaging technique to detect deficits in what may be an elemental neurobiological mechanism that allows us to distinguish our own thoughts and actions from those of others. We hope to determine whether it runs in families, is present early in the illness, and is stable and reliable.